Recent advances in the understanding of certain mutations which underlie familial Alzheimer disease (AD) have opened new approaches to the development of appropriate small animal models for this neurodegenerative disorder. The characterization of the AD genetic loci on chromosomes 14 and 1 has led to the discovery of two highly related proteins, presenilin-1 (PS-1) and presenilin-2 (PS-2), in which numerous mutations have been linked to early-onset AD in some families. The P.I. has successfully generated transgenic mice which express various forms of PS-1 (including mutant and wild type proteins) under the control of the platelet-derived growth factor B-chain promotor. These mice represent an attempt to model the early-onset AD caused by these mutations and to assess the consequences of the over-expression of both wild type and mutant forms of these proteins. One major criterion by which these animals can be evaluated as an adequate model for AD is whether the transgene leads to AD-like pathologic findings. Thus, the first Specific Aim of this project is to investigate the neuropathologic consequences of the over-expression of various forms of PS-1 in the brains of these transgenic mice. These mice also have the potential to serve as a source of neuronal tissue for use in cell culture experiments. Such experiments can elucidate the consequences of these forms of PS-1 on cellular functioning and in response to a wide variety of exogenous influences. It is first critical, however, to determine when, during tissue culture, and from which brain regions the transgene is active. Thus, the second Specific Aim of this project is to characterize the expression of PS-1 transgenes in primary neuronal cultures of various brain regions from these animals. The combined outcome of these experiments will be the characterization of these animals at the intact brain level and as a potential source for cultured primary neurons. Through the detailed analysis of this model system for AD at both of these levels, it may become possible to use this a system to evaluate the effects of possible therapeutic interventions for this devastating neurodegenerative disorder.